Unwanted blood clotting can trigger serious health concerns like heart attacks and strokes, but treatment with blood thinners comes with the risk of uncontrolled bleeding. After all, blood clotting is an essential part of wound healing. That means that a tight balance between the two extremes is needed to slow clotting down just enough, and presently that involves careful monitoring to achieve the right dose for each patient.
That’s because blood thinners used clinically today — like heparin and warfarin — disrupt the activity of enzymes that are essential to clotting. Too little, and unwanted clots can still form; too much, and the risk of complications rises.
New research by researchers at the University of British Columbia and University of Michigan takes a different approach by targeting a molecule that accelerates clotting but isn’t essential to it. Even if the target is completely neutralized, clotting can still proceed — just more slowly. Their development of a clotting inhibitor called MPI 8 was published in Nature Communications.
“The development of MPI 8 represents a major breakthrough in the field of blood clot prevention and treatment,” said principal investigator Jay Kizhakkedathu, professor of pathology and laboratory medicine at UBC, in a press release.
“By targeting a specific molecule involved in clot formation without disrupting the natural clotting process, we’ve created a blood thinner that has proven safer and more effective in animal models, with enormous potential to improve human lives as well.”
MPI 8 is a large and branching molecule that takes advantage of the attraction between opposite charges to draw in its target. The target is polyphosphate (polyP), a polymer strand that has many negative charges along its length.
To be biocompatible and stay in the body long enough to work, MPI 8 is mainly charge neutral at physiological pH, with only a minimal positive charge. On binding polyP, more positive charges are induced locally to help hold onto polyP tightly.
Notably, the exact composition of MPI 8 makes this interaction selective enough that other negatively charged cells and proteins are not affected, preventing possible toxic side effects.
In pre-clinical models of clotting, MPI 8 was effective in preventing blood clots in mice without increasing their risk of bleeding. Even at high doses, the researchers didn’t see signs of toxicity, meaning a wider range of doses can be used for treatment without side effects.
This approach to restoring balance in the body’s processes has a lot of potential in medicine. Additional pre-clinical testing is still ongoing, with the ultimate hope to validate this strategy in human clinical trials.
